Snapshot: What are Caenorhabditis elegans models?

What are C. elegans?

If you read the title of this article and had no idea what Caenorhabditis elegans are, you are not alone! Caenorhabditis elegans, more commonly known as C. elegans, are microscopic worms that typically grow up to 1 mm in length. C. elegans are naturally found worldwide in soil where there is rotting vegetation. If you are feeling brave, you can try to locate them in your household compost! Although these worms are less familiar to the general public, C. elegans are well known to scientists, since studying these tiny worms has taught us a lot about human disease.

Why are C. elegans used as a model system?

C. elegans were first isolated in 1900 and, since the late 1960s, have been used to “model” human disease. This is because C. elegans and humans share some common physiological features and have a significant overlap in their genetic codes. SCAsource previously published a Snapshot on mouse models, which are widely used in ataxia research,. Although C. elegans are not used as widely in ataxia research, there are many advantages to using C. elegans as a model system:

  • C. elegans are inexpensive to maintain, allowing for the screening of thousands of drugs at a relatively low cost. Once administered, scientists can study the drugs’ effects on C. elegans movement, development, and nervous system function.
  • C. elegans are easy to grow in the laboratory.
  • C. elegans are self-fertilizing hermaphrodites, meaning that they can reproduce without a sexual partner. A single hermaphrodite can produce 300-350 offspring over a 3-day period, allowing scientists to easily study a large number of worms that have the same genetic characteristics.
  • Scientists can easily manipulate the genome of C. elegans to study many human diseases.
  • Because C. elegans are transparent, their internal organs, including the nervous system, can be imaged without dissection.

How can C. elegans be used to study neurodegeneration?

The nervous system of a C. elegans is made up of a few hundred neurons, which is relatively simple compared to the human brain (which contains about 86 billion neurons). Because of this simplicity, scientists have used C. elegans to develop models for several neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Friedreich’s ataxia and, more recently, spinocerebellar ataxia type III (SCA3). The SCA3 C. elegans model was developed by a research group in Portugal led by Dr. Patrícia Maciel, and it is the first of its kind in the spinocerebellar ataxia field. These worms express the human SCA3-causing protein in all their neurons, resulting in adult-onset motor dysfunction that resembles what we see in SCA3 patients.

a microscope image of neurons in two c. elegans worms. One is a smooth, healthy neuron. One has a damaged neuron that has a break in it.
A microscopy image of C. elegans neurons coloured green. Image courtesy of Kim Pho.

Neurodegeneration (damage/death of neurons) in C. elegans is monitored by tagging neurons with a marker that shines green under a specific type of light. The health of neurons is then assessed, making it possible to determine if neurodegeneration has occurred. The image above shows a healthy C. elegans neuron on the left, which appears intact, compared to a damaged C. elegans neuron on the right, which has a break (white arrowhead). Being able to distinguish between healthy and damaged neurons in C. elegans is very useful, as scientists can use this tool to test different ways of repairing or protecting neurons. If scientists are able to slow or prevent neurodegeneration in C. elegans, there is potential that such a discovery could eventually help treat human neurodegeneration, as well.

I hope this short summary has shown you that there is a massive amount of scientific potential in these tiny worms! Understanding the biology of C. elegans provides insight into human biology, like how neurodegeneration occurs and what we can do to stop it.

If you would like to learn more about C. elegans model systems, take a look at WormBook, Wormbase, and WormAtlas.

Thank you to Kim Pho from Dr. Lesley MacNeil’s lab at McMaster University for providing the fluorescent images of C. elegans neurons.

Snapshot written by Katie Graham and edited by Dr. Lesley MacNeil.

A Potential Treatment for Universal Lowering of all Polyglutamine Disease Proteins

Written by Frida Niss Edited by Dr. Hayley McLoughlin

One drug to treat them all: an approach using RNA interference to selectively lower the amount of mutant protein in all polyglutamine diseases. Work by a group in Poland shows initial success in Huntington’s Disease, DRPLA, SCA3/MJD, and SCA7 patient cells.

Can one drug treat nine heritable and fatal disorders? Polyglutamine diseases are disorders in which a gene encoding a specific protein is expanded to include a long CAG repeat. This results in the protein having a long chain of the amino acid glutamine, which disturbs the ability of the protein to fold itself and interact correctly with other proteins. This type of malfunctioning protein would normally be degraded by the cell, but in the case of polyglutamine proteins this seems unusually difficult. This causes a gradual build-up of faulty protein that disrupts several cellular pathways, eventually leading to cell death in sensitive cells. Currently there is only symptomatic treatment of these fatal diseases available, and they do not slow down the disease progression. One promising line of research is investigating the possibility of lowering the amount of these disease proteins using RNA interference.

RNA interference is the method by which a gene is silenced through a manipulation of a natural defense mechanism against viruses. When a virus attacks, it tries to inject DNA or RNA like particles to hijack the cell’s machinery for its own survival. To defend itself, the cell uses the RNA interference pathway, where the protein Dicer slices the DNA/RNA into smaller pieces and loads it into the RNA-induced silencing complex (RISC complex). The RISC complex finds all DNA/RNA particles in the cell with the same sequence and destroys them, effectively hamstringing the virus.

This machinery can be co-opted as a potential tool for treating neurodegenerative diseases caused by harmful mutant proteins. By inserting a small interfering RNA (siRNA), we can target the mRNA that codes for the harmful protein and trick the RISC complex into degrading it. In polyglutamine diseases, this has been successful when the mutant mRNA possesses a small mutation called a single nucleotide polymorphism (SNP). However, when an siRNA is delivered to a cell using a vector, which is a circular piece of DNA carrying genetic material, the Dicer protein tends to process the siRNA in unpredictable ways. This means that the treatment may not always be selective, and can end up targeting the normal protein as well. Moreover, not all patients have the same SNPs, so several drugs for every disease might be needed.

A pipette transfering liquid between small centifuge tubes
Close up picture of scientific research being conducted in a laboratory. Image courtesy of the University of Michigan SEAS.

In the paper by Kotowska-Zimmer and colleagues they have used short hairpin RNAs (shRNAs) targeting the CAG repeat tract itself instead of siRNAs targeting SNPs around the CAG repeat tract. shRNAs fold themselves like a hairpin when transcribed, and this loads them into the RISC complex through a somewhat different pathway, with less degradation along the way than conventional siRNAs. The second part that is different to other RNA interference strategies in this study is that the shRNA does not completely match the CAG repeat, but contains mismatches. This means that the RISC complex cannot actually cut and degrade the mRNA, and ends up simply sitting on the CAG repeat tract instead. The longer the repeat tract, the more RISC complexes can fit on the tract and block translation. Using this type of RNA interference Kotowska-Zimmer and colleagues have tried to lower the expression of huntingtin, atrophin-1, ataxin-3 and ataxin-7 proteins in cellular models of the corresponding polyglutamine diseases.

Continue reading “A Potential Treatment for Universal Lowering of all Polyglutamine Disease Proteins”

Gene Therapy Validated In Human SCA3 Stem Cells

Written by Dr. Marija Cvetanovic Edited by Dr. Sriram Jayabal

Research group in Michigan report the creation of the first NIH-approved human cell model that mirrors SCA3 disease features – cellular defects that, after gene therapy, show improvement

Spinocerebellar ataxia type 3 (SCA3) is a dominantly-inherited, late onset genetic disease that affects multiple brain regions. Affected individuals suffer from several symptoms, with impaired movement coordination being the most debilitating. SCA3 is caused by a mutation in the Ataxin-3 (ATXN3) gene. In unaffected individuals, ATXN3 typically has anywhere from 12 to 44 repeats of the genetic code “CAG;” however, in some people’s genetic code, the number of CAG repeats can become abnormally high. If this “repeat expansion” mutation causes the ATXN3 gene to have more than 56 CAG repeats, the person develops SCA3. Cells use repeating CAG sequences in their genome to make proteins with long tracts of the amino acid glutamine. In SCA3 cells, these “polyglutamine” (polyQ) tracts are abnormally long in the ATXN3 protein, which makes the protein more prone to form clumps (or “aggregates”) in the cell. The presence of these protein clumps in the cells of the brain is one of the hallmarks of SCA3.

Despite knowing the genetic cause of SCA3, it is still not known how this mutation affects cells on the molecular level. Having said that, several cellular and animal models have been developed in the past two decades to help study these underlying mechanisms. SCA3 models have not only helped to  our increased understanding of the disease’s progression at all levels – molecular, cellular, tissue, and behavioral – but also helped move us closer to therapeutic interventions. For instance, recent studies using SCA3 mouse models have established that targeting ATXN3 with a form of gene therapy known as antisense oligonucleotide (ASO) treatment could very well be an effective strategy for improving the lives of patients. ATXN3-targeting ASOs cause the cells of the brain to produce less of the mutant ATXN3 protein and, when given to SCA3 mice, improved their motor function. These results strongly support the potential use of ASOs to treat SCA3. Still, it is important to see if this finding can be repeated in human neurons (a step that is needed to bring us closer to ASO clinical trials).

Female scientist in a while lab coat busy at work, we are looking at her from behind through some glass bottles
Image of a research scientist hard at work in the lab. Image courtesy of pxfuel.

Previous experience from unsuccessful clinical trials highlight the importance of determining the similarities and differences between humans and mice when it comes to disease. For instance, the SCA3 mutation does not naturally occur in mice; therefore, modeling SCA3 with mice usually requires additional genetic manipulation, which could lead to unexpected effects that we do not typically see in patients. In addition, we may miss important determinants of SCA3 pathology due to the inherent differences between humans and mice. For example, proteins that help contribute to SCA3 in human patients may simply not be present in mouse neurons (and vice versa). Because of such species differences, the therapeutic interventions that are effective in mice are not always as effective in humans.

SCA3 human neurons can help bridge the gap between rodent models and human patients, acting as a clinically relevant tool for looking into disease mechanisms and testing new therapies. Because we cannot remove a portion of an SCA3 patient’s brain to study the disease, these neurons must be created in a lab. Human neurons can be generated from induced pluripotent stem cells (iPSCs) or from human embryonic stem cells (hESCs). Induced pluripotent stem cells (iPSCs) are made from adult cells (usually blood or skin cells) that are reprogrammed to return to an embryo-like form (known as the “pluripotent” state). Just like during normal development, iPSCs can create many different types of cells, including neurons. One problem with this approach is that the process of reprograming can potentially change these cells in way that could affect how the disease presents. To avoid this issue, researchers can also create human neurons from human embryonic stem cells (hESCs), which are derived from embryos and are, therefore, naturally pluripotent. Because hESCs do not require reprograming, they are more likely to accurately model disease. However, they are more difficult to obtain and work with. The researchers in this study, led by Lauren Moore in Dr. Hank Paulson’s lab at the University of Michigan, used hESCs to generate the first ever National Institutes of Health (NIH)-approved SCA3 model using human cells.

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Snapshot: What are single nucleotide polymorphisms (SNPs)?

It’s in our DNA

If you were to unravel the tightly wound packages of our genome known as chromosomes, you would find long strings of DNA. The strings are made up of only four different building blocks, compounds abbreviated as adenine (A), thymine (T), guanine (G) and cytosine (C). Picture a ridiculously long hospital baby bracelet made only of beads bearing the letters A, T, C, and G.

handmade bead bracelet. Each bead has either "A", "T", "C", or "G" on it. It represents the genetic code that is DNA.
Bead bracelet of A, T, G, and C bead. Image courtesy of Tamara Maiuri.

Our genes are simply stretches along the string of DNA–regions where the order of the compound “beads” is especially important. Genes are the blueprints that code for all the materials needed by our cells. Changes in the order of the building blocks (or, in the case of many spinocerebellar ataxias (SCAs), the addition of too many C-A-Gs), can result in faulty gene products, which can cause disease.

But we can’t all be walking around with identical DNA sequences, like an army of clones! What makes us different? One difference is the small, less consequential changes in the order of the building blocks: variations that usually occur in regions of the DNA between genes, which aren’t critical to gene function.

One such type of variation is called a single nucleotide polymorphism (SNP, pronounced “snip”). Nucleotide is the scientific name for the A, T, C, and G compounds. Polymorphism derives from poly (many) and morph (forms). So a SNP is a change at a single position in the DNA, for example from an A to a C.

Why are SNPs important?

SNPs have been hugely beneficial in helping scientists figure out which genes are linked to disease by acting as biological markers that track with disease genes within families. They may also play a role in therapeutic strategies to lower disease-causing proteins such as the Ataxin proteins that cause some SCAs. SCAsource has previously covered ASO therapy and the clinical trials happening for Huntington’s disease. How can SNPs help with ASO therapies?

ASO therapies are based on the idea of blocking toxic protein production from the inherited disease gene, or “shooting the messenger”. The trouble with this strategy is that everyone actually has two copies of each gene in the genome: one from Mom and one from Dad. Sometimes we don’t necessarily want to block both copies because these genes, when functioning normally, have essential jobs to do in the cell. The ideal situation would then be to block the production of the toxic copy and leave the good copy alone.

For most SCAs, the toxicity comes from the expanded CAG region of the gene. So why not target the extra CAGs? The main problem is that a handful of other genes also have stretches of CAGs. So the drug would have off-target effects. But SNPs lying close to a disease gene are usually inherited along with it. These SNP sites can be targeted by ASO drugs, allowing the drugs to hone in on the toxic copy. The drawback is that these drugs wouldn’t work for people who don’t have the right SNP attached to their disease gene (or who have the same SNP on both copies of the gene).

In summary, just as SNPs tracking with a disease gene helped identify the causes of many genetic diseases, they may also help in their treatment. Vive la difference!

If you would like to learn more about Single Nucleotide Polymorphisms (SNPs), take a look at these resources by the Encyclopedia Brittanica and National Human Genome Research Institute.

Snapshot written by Dr. Tamara Maiuri and edited by Dr. Hayley McLoughlin.

Working with cerebellar ataxia

Written by Dr. David Bushart Edited by Dr. Sriram Jayabal

How can employment be made more accessible for ataxia patients? What barriers exist? A study of workers and non-workers with ataxia analyzes the benefit of employment, as well as how to reduce risk of injury.

A job can often become part of a person’s identity. When people meet for the first time, one of the first questions that often comes up is “what do you do for work?” While this question can be harmless, it can also be frustrating to non-workers, particularly to those who are actively looking for employment. This may include some patients with cerebellar ataxia.

It can be difficult to manage disease symptoms alongside the stress of a job. However, some patients may find that including a job as part of their routine can be helpful for physical and mental wellness. In these cases, it is important for ataxia patients to have access to fair employment. Despite these benefits, finding a job can prove quite challenging, and unfortunately, ignorant assumptions about the capabilities of workers with ataxia may make finding employment even harder. How can employment be made more accessible to ataxia patients who wish to work?

two people shaking bands over a business agreement
Photo by fauxels on

Determining the work capabilities of ataxia patients

Helping ataxia patients find work might have a significant benefit on their overall quality-of-life. Researchers in Italy designed a study to get a better idea about the capabilities of workers with ataxia and the barriers to employment that they face. The research team, led by Alberto Ranavolo, interviewed both workers and non-workers with ataxia. Importantly, the patients interviewed for this study had been diagnosed with different types of ataxia, including dominantly-inherited ataxias, Friedrich’s ataxia, and other ataxias with unknown causes. Within this group, 24 were currently workers and 58 were non-workers at the time of the study. This allowed the researchers to determine how characteristics such as age, gender, education, and duration of symptoms might impact the ability to work.

Continue reading “Working with cerebellar ataxia”